WO1999016480A1

WO1999016480A1 - Biological fluid processing

Info

Publication number: WO1999016480A1
Application number: PCT/GB1998/002942
Authority: WO
Inventors: Ian Swann
Original assignee: Pall Corporation
Priority date: 1997-10-01
Filing date: 1998-10-01
Publication date: 1999-04-08
Also published as: GB9720867D0; GB2329848A8; GB2329848A; AU9273798A

Abstract

Systems and methods provide for creating a pressure differential and simultaneously compressing a biological fluid in a first container and a non-biological fluid in a second container, wherein the non-biological fluid is compatible with the biological fluid.

Description

BIQI.0OTC.ftIi FLUID PROCESSING

This invention relates to the processing of a biological fluid such as whole blood, especially to deplete leukocytes from the components of the biological fluid. Blood has a variety of components, particularly red blood cells (erythrocytes) , platelets, and plasma, that can be used separately, e.g., as transfusion products. Blood also contains white blood cells (leukocytes) , and the transfusion products may be depleted of leukocytes before transmission into a recipient . Typically, blood is collected from a donor into a plastic blood collection bag, wherein the bag is part of a blood collection set including additional bags, and including one or more additive solutions . The blood collection set may also include at least one leukocyte depletion filter. After the blood is collected it is centrifuged to separate the components in the bag according to their differences in densities .

For example, the centrifuged blood can form an upper layer containing most of the plasma, an intermediate layer (sometimes known as the buffy coat) containing the majority of the platelets, as well as plasma and some red and white blood cells, and a lower layer containing the majority of the red blood cells. Alternatively, the centrifuged blood can form an upper layer of platelet rich plasma (PRP) and a lower layer containing the majority of the red blood cells. A pressure differential is then created, e.g., by compressing the collection bag, and one or more layers is passed from the collection bag into one or more additional (satellite) bags. Some protocols include passing the layer (s) through a leukocyte depletion filter interposed between the bags to provide leukocyte-depleted blood components.

The blood components can be further processed, e.g., to produce platelet concentrate (PC) . For example, a satellite bag containing platelet rich plasma or buffy coat is centrifuged to concentrate the platelets at the lower portion of the bag, and a pressure differential is created to pass the majority of the plasma to another satellite bag. Additionally, blood components (typically platelets and/or red blood cells) can be combined with an additive solution, e.g. to maintain the viability of the components during storage.

A variety of expressors can be used to create the pressure differential (s) for passing the components and/or additive solutions from one bag to another. For example, some expressors include a support surface and one or more movable plates that compress the collection bag after the collection bag is inserted between the support surface and the plate (s) .

Illustratively, a collection bag having ports at the top and at the bottom can be compressed by a movable plate to express the upper plasma layer through the upper port, and to express the lower red cell layer through the lower port. Alternatively, one or more movable plates can compress the collection bag to pass the components through a single port (e.g., a top port) of the bag.

Some of these expressors for creating the pressure differential have been awkward, labor intensive and/or time consuming to operate. For example, it may require a number of separate steps to pass an additive solution from one bag to another to mix the appropriate solution with the appropriate blood component . These steps can be time consuming to carry out . Additionally, or alternatively, a number of expressors are not designed to be efficiently used with some blood bag set configurations, e.g., sets including a filter for depleting leukocytes from the red cells, since, for example, it may be awkward, difficult, and/or time consuming to prime the filter. Accordingly, some blood processing protocols include priming the filter without using the expressor. Illustratively, after the plasma and red cells have been passed from the collection bag, the set is typically removed from the expressor and the red cell filter is primed by hand, e.g., by manually compressing the bag containing the mixture of red cells and additive solution to pass the mixture through the filter and into a transfer bag, or the filter may be reverse primed as the additive solution passes into the red cell bag by gravity. The fluid mixture of red cells and additive solution is then filtered by passing it through the leukocyte depletion filter device by gravity. The present invention provides for ameliorating at least some of the disadvantages of the prior art . These and other advantages of the present invention will be apparent from the description as set forth below.

In accordance with the invention, there is provided a method for processing a biological fluid comprising simultaneously compressing a first container and a second container with a single pressure differential, the first container including a biological fluid, and the second container including a non-biological fluid, wherein the non-biological fluid is compatible with the biological fluid.

The following is a more detailed description of some embodiments of the invention, by way of example, reference being made to the accompanying drawings, in which:

Figure 1 is an illustration of an arrangement for simultaneous expression of biological fluid from a first container, and non- biological fluid from a second container, wherein the containers are part of a biological fluid processing set that also includes a leukocyte depletion filter device, as well as a third container and a fourth container, Figure 2 is an illustration of another arrangement for simultaneous expression of biological fluid from a first container, and non-biological fluid from a second container, wherein the containers are part of a biological fluid processing set that also includes a leukocyte depletion filter device, as well as a third container and a fourth container,

Figure 3 is an embodiment of the biological fluid processing set shown in Figures 1 and 2.

A method for processing a biological fluid according to an embodiment of the invention comprises creating a pressure differential and simultaneously passing at least a portion of biological fluid from a first container, and at least a portion of a non-biological fluid from a second container, wherein the non- biological fluid is compatible with the biological fluid.

Another embodiment of a method for processing a biological fluid according to the invention comprises simultaneously compressing a first container including a biological fluid, and a second container including a non-biological fluid, wherein the non- biological fluid is compatible with the biological fluid.

In preferred embodiments, a method according to the invention includes passing the non-biological fluid through a biological fluid filter device interposed between the first container and the second container .

In accordance with yet another embodiment of the invention, a method for processing biological fluid comprises obtaining a biological fluid processing system, the system comprising: at least a first container, a second container, and a third container, the first container including a biological fluid, and the second container including a non-biological fluid, wherein the non- biological fluid is compatible with the biological fluid; a biological fluid filter device, interposed between the first container and the second container; creating a pressure differential, and passing simultaneously; at least a portion of the biological fluid from the first container, and at least a portion of the non-biological fluid from the second container and through the biological fluid filter device. Typically, embodiments of the method according to the invention include forming a fluid mixture composing a non-biological fluid and at least a portion of the biological fluid, and passing the mixture through a biological fluid filter device such as a leukocyte depletion device. In accordance with an embodiment of the invention, a biological fluid processing set is provided comprising a first flexible plastic bag suitable for holding a biological fluid, the bag having at least one top port and at least one bottom port; a second flexible plastic bag suitable for holding a unit of biological fluid additive solution; a biological fluid filter device, interposed between the first and second bags; wherein the bag set lacks an air removal loop. In a preferred embodiment, the filter device comprises a leukocyte depletion device. In an even more preferable embodiment, the set further comprises at least a third flexible bag, the third bag being suitable for holding at least a portion of biological fluid, and at least a portion of the additive solution, wherein the biological fluid is compatible with the additive solution, said third bag being interposed between the first bag and the leukocyte depletion filter device.

The following definitions are used in this specification:

(A) Biological Fluid. A biological fluid includes any treated or untreated fluid associated with living organisms, particularly blood, including whole blood, warm or cold blood, and stored or fresh blood; treated blood, such as blood diluted with at least one physiological solution, including but not limited to saline, nutrient, and/or anticoagulant solutions; blood components, such as platelet concentrate (PC) , plateletrich plasma (PRP) , platelet-poor plasma (PPP) , platelet-free plasma, plasma, fresh frozen plasma (PFP) , components obtained from plasma, packed red cells (PRC) , buffy coat (BC) ; analogous blood products derived from blood or a blood component or derived from bone marrow; red cells separated from plasma and resuspended in physiological fluid; and platelets separated from plasma and resuspended in physiological fluid. The biological fluid may have been treated to remove some of the leukocytes before being processed according to the invention. As used herein, blood product or biological fluid refers to the components described above, and to similar blood products or biological fluids obtained by other means and with similar properties . A "unit" is the quantity of biological fluid from a donor or derived from one unit of whole blood. It may also refer to the quantity drawn during a single donation. Typically, the volume of a unit varies, the amount differing from donation to donation. Multiple units of some blood components, particularly platelets and buffy coat, may be pooled or combined, typically by combining four or more units . (B) Non-Biological Fluid. A non-biological fluid is a fluid that substantially lacks, or completely lacks, red blood cells, white blood cells, platelets, and plasma, wherein the non-biological fluid is compatible with a biological fluid. Typical non-biological fluids include a physiological solution, including but not limited to additive solutions such as saline, nutrient, and/or anticoagulant solutions. Preferred additive solutions are storage solutions, e.g., for maintaining the viability of blood components such as red blood cells and/or platelets during storage. Each of the components of the embodiments will now be described in more detail below, wherein like components have like reference numbers .

EXPRESSOR A variety of expressors are suitable for carrying out the invention. For example, the expressor can include an enclosed or non-enclosed housing that accommodates the containers. Typically, the expressor is automated, or semi-automated. The expressor can include one or more flow control devices such as clamps or valves, e.g., to prevent or allow flow through a specific conduit in the biological fluid processing set . The expressor can also include one or more sensing devices, e.g., at least one of a flow sensor, a weight sensor, and an optical sensor.

In an embodiment, as shown in Figure 1, an expressor 200 comprises an open or non-enclosed housing 201 providing a space 205 for accommodating at least two variable volume containers, i.e., a variable-volume container of biological fluid 1, and a variable volume container of non-biological fluid 2. The expressor includes a support surface 202 and a movable plate 203, wherein the outer surface of the support 202a and the inner surface of the movable plate 203a define the space for accommodating the variable volume containers . The expressor can include attachments to further define the space for accommodating the containers, e.g., one or more additional plates on the outer surface of the support and/or the inner surface of the movable plate.

The embodiment of the expressor shown in Figure 1 creates a pressure differential when the movable plate 203 moves toward the support-surface 202. As the space 205 between the support and movable plate is reduced, the containers 1,2 are compressed, and fluid can be passed from each container. In accordance with the invention, at least a portion of biological fluid passes from the first container 1 while a portion of non-biological fluid passes from the second container 2.

In some embodiments, the initiation of fluid flow from each container is simultaneous, or nearly simultaneous. In other embodiments, the initiation of fluid flow from each container is not simultaneous .

If desired, the initiation of fluid flow from a specific container or through a specific port of the container can be separately controlled. For example, one or more flow control devices (e.g., valves or clamps) can be associated with individual conduits, and the flow control device (s) can be opened at the appropriate point to allow fluid flow. Accordingly, in those embodiments wherein the initiation of flow from each container is not simultaneous or nearly simultaneous, fluid flow can be controlled so that flow is simultaneous at some point while carrying out the invention. Typically, the flow from the first and second containers is simultaneous for about 3 seconds or more. For example, the flow can be simultaneous for about 5 seconds to several minutes.

Illustratively, in one embodiment of the invention, the flow of at least a portion of the biological fluid (e.g., plasma) from the first container 1 and the flow of non-biological fluid (e.g., an additive fluid such as a red cell storage solution) from the second container 2, is simultaneous for about 5 seconds to about 30 seconds, although the biological fluid flows for about 70 seconds or more, and the non-biological fluid flows for about 45 seconds or less .

Of course, flow from either container 1,2 can be interrupted and/or terminated as desired, as long as the flow from the first and second containers 1,2 is simultaneous at some point while carrying out the invention.

Suitable expressors having an open housing include, but are not limited to, those disclosed in U.S. Patent No. 4,350,585, or commercially available under the tradenames Optipress I™, Optipress II™, (both available from Baxter, International) ; BSS II™, BSS III™ (both available from the Austrian Red Cross) ; and the Compomat G3^® and G4^® (both available from NPBI) . Many of these expressors include at least one flow control device and at least one sensing device.

In another embodiment as shown in Figure 2, an expressor 300 comprises a housing 301 defining an enclosed chamber 305 for accommodating at least two variable volume containers i.e., the containers of biological fluid 1 and non-biological fluid 2. The housing 301 has at least one opening 302 through which at least two conduits, e.g., the conduits 22,24 connected to the variable-volume containers, and an opening 303 through which at least another conduit 25 connected to variable-volume container 1 can extend. Typically, the expressor 300 includes a pressure regulating mechanism communicating with the housing 301 to vary the pressure of fluid in the chamber exterior to the containers, and thus vary the volume of the containers .

The embodiment of the expressor 300 shown in Figure 2 creates a pressure differential (the pressure can be positive or negative) , and fluid can be passed from each container 1,2. At least a portion of biological fluid passes from the first container 1 while a portion of non-biological fluid passes from the second container 2. The initiation of fluid flow from each container can be simultaneous, or sequential, as described earlier. Furthermore, flow from either container can be interrupted and/or terminated as desired, as long as the flow from the first and second containers is simultaneous at some point while carrying out the invention.

Suitable expressors having an enclosed housing include, but are not limited to, those disclosed in U.S. Patent No. 5,547,108, International Publication No. WO 94/01193, U.K. Patent Nos . 2,284,909, and 2,298,933, or commercially available from Pall Corporation. These expressors can include at least one flow control device and/or at least one sensing device. THE BIOLOGICAL FLUID PROCESSING SET

The biological fluid processing set 100, which can be closed or open, includes one or more containers and one or more conduits providing fluid communication between the containers . One preferred set includes four or more containers (1-4) , and six or more conduits

(20-25) .

As will be noted in more detail below, the set typically includes at least one filter device 10, especially a leukocyte depletion filter device, interposed between two of the containers, and also includes at least one flow control device such as a seal, clamp, valve, or transfer leg closure.

In some embodiments, the set includes additional elements such as, but not limited to, at least one of: a gas inlet, a gas outlet, a gas collection and displacement loop, and a bypass loop. However, the embodiment of the set illustrated in Figure 3 lacks any one of gas inlet, a gas outlet, a gas collection and displacement loop, or a bypass loop.

The elements which are used in the biological fluid processing set are constructed of any material compatible with a biological fluid and gas or air. At least some of the elements used in the set are also compatible with a non-biological fluid such as an additive solution. Preferably, the set is capable of withstanding centrifugation. CONTAINERS and CONDUITS A wide variety of suitable containers (1-4) and conduits (20-

25) are known in the art. For example, containers such as blood collection and satellite bags are typically made from plasticised polyvinyl chloride, e.g. PVC plasticised with dioctylphthalate, diethylhexylphthalate, or trioctyltrimellitate. The bags may also be formed from polyolefin, polyurethane, polyester, and polycarbonate .

The conduits are any tubing or means which provides fluid communication between the containers, and are typically made from the same flexible material as is used for the containers e.g., plasticized PVC. The containers include at least one port, and can include multiple ports, e.g., at the top and bottom of a container. Containers may be modified according to an intended use. For example, the containers may include at least one internal passageway to allow fluid to flow to or from a particular portion of the container located near the passageway. The container may be segmented, compartmentalized and/or enlarged, typically to provide for isolation of a portion of the biological fluid, e.g., for sampling. One or more conduits may extend into the interior of the container (s) . There may be a number of conduits providing fluid communication to any individual container, and the conduits may be located in a number of ways. For example, there may be at least two conduits located at the top of the collection bag, or at the bottom of the bag, or a conduit at each end of the bag, or a conduit extending from an intermediate portion of the bag.

Included within the scope of the present invention are variations on any of these configurations of containers and/or conduits .

FILTER DEVICE

A filter device 10 comprises a housing having first port and a second port and defining a fluid flow path between the first port and the second port, and a filter comprising a porous medium interposed between the first port and the second port and across the fluid flow path. In a preferred embodiment of the invention, the filter device allows bidirectional fluid flow therethrough, e.g., biological fluid passes from the first (or "inlet") port through the porous medium and the second (or "outlet") port, and non-biological fluid passes from the second port through the porous medium and the first port. In this context, the terms "inlet" and "outlet" are used for reference without so limiting the invention, since a port can be an "inlet" for one fluid and an "outlet" for another.

Preferably, the filter device is a leukocyte depletion device, and the filter comprises a porous leukocyte depletion medium. Suitable leukocyte depletion media include synthetic, polymeric media, including, but not limited to, fibrous media, especially media prepared from melt-blown fibers. The filter can include additional media and/or elements, e.g., for support, drainage, gel removal, and/or microaggregate removal.

A variety of suitable filter devices and filter media, especially leukocyte depletion media, are known in the art. Suitable devices and media include those disclosed in, for example, U.S. Patent Nos . 4,880,548; 4,925,572, 5,152,905, and 5,443,743. The leukocyte depletion medium can be treated for increased efficiency in processing a biological fluid. For example, the medium may be surface modified to affect the critical wetting surface tension (CWST) of the medium, as described in, for example, the U.S. Patents listed above. Typically, embodiments allow a portion of non-biological fluid to pass from a second container and through a filter device before a portion of the biological fluid passing from the first container reaches the filter device. Illustratively, this can be accomplished by at least one of controlling fluid flow through one or more conduits, providing a longer fluid flow path between the first container and the device than between the second container and the filter device, and interposing at least one additional container between the filter device and the first container.

For example, as shown in Figure 3, the biological fluid processing set 100 can include at least four containers (e.g., a first container 1 holding a biological fluid, a second container 2 holding a non-biological fluid, a third container 3, and a fourth container 4) and a filter device 10, wherein the filter device 10 is interposed between the second container 2 and the third container 3, and the third container 3 is interposed between the filter device 10 and the first container 1. The biological fluid processing set 100 is then associated with an expressor as show in Figures 1 and 2.

Accordingly, after the first container 1 and the second container 2 are placed in the housing of the expressor, a pressure differential is generated, thus causing fluid flow. The non- biological fluid passes from second container 2 through conduit 24, device 10, and conduit 23 into another (third) container 3. At approximately the same time, the fourth container 4 fills with a portion of biological fluid passing from the first confiner 1 and through conduit 25. Subsequently, third container 3 fills with a portion of biological fluid passing from the first container 1 and through conduit 22. The non-biological fluid contacts the biological fluid in the third container 3, e.g., to form a fluid mixture. Typically, the third container 3 is then removed from the housing of the expressor, and the fluid mixture, i.e., comprising the biological fluid and the non-biological fluid, is passed from the third container 3 , and through the leukocyte depletion filter device 10 to deplete leukocytes from the biological fluid. In accordance with the embodiment shown in Figure 3 , since the second container 2 is essentially empty after the non-biological fluid is passed therefrom, another pressure differential is generated, and the mixture is passed from the third container 3 through the leukocyte depletion device 10, and into the second container 2. Example

A blood processing set is provided as shown in Figure 3, and placed in an expressor as shown in Figure 1.

The set 100 includes 4 plastic blood bags, a leukocyte filter device, and a plurality of plastic conduits forming a closed system. The blood collection bag 1 is a commercially available top and bottom bag, and the other bags, i.e., the SAGM additive bag 2, the transfer 3, and the plasma bag 4, are commercially available top port bags. The conduits 20-25 are commercially available plastic tubing. The leukocyte filter device 10 is a red cell filter commercially available from Pall Corporation.

The set also includes a clamp associated with conduit 23. The collection bag 1 contains a centrifuged unit of whole blood (about 450 ml of blood and about 63 ml anticoagulant) , and the SAGM bag 2 initially includes about 100 cc of SAGM additive solution. The set 100 is loaded onto a commercially available automated expressor 200 that includes a movable pressure plate 203 and a fixed support plate 202. The expressor includes optical sensors (not shown) for sensing the level of buffy coat in the collection bag, and for sensing the presence of red cells in conduit 25.

As illustrated in Figure 1, the SAGM additive bag 2 and the collection bag 1 are mounted onto the bag pins of the expressor 200, and the leukocyte filter device 10 is mounted, using a filter holder, on the side of the expressor, with the SAGM bag kept below the height of the filter device, and the port of the SAGM device facing downward. The plasma bag 4 is placed on top of the expressor 200, and the transfer bag 3 is hung, inverted from a hook incorporated into the filter holder.

The transfer leg closure for the SAGM bag, as well as those for the top (plasma) and bottom (red cell) ports of the collection bag are opened, and the machine is activated as per standard procedure .

As the movable pressure plate compresses the collection bag 1 and SAGM bag 2, SAGM is passed from the additive bag 2, through conduit 24 and the filter device 10 (entering via the outlet and exiting via the inlet) , and into the transfer bag 3. Additionally, plasma passed from collection bag 1, through conduit 25 into plasma bag 4. The additive fluid primes the filter device 10 before the automatic red cell clamp opens to allow a significant volume of red cells to pass from the collection bag 1 and through conduit 22 into the transfer bag 3. The flow of additive fluid from the additive bag 2, and the flow of plasma from the collection bag 1, is simultaneous for about 10-15 seconds. Within about 30 seconds the SAGM additive bag 2 is essentially empty. The machine operates to continue to express the plasma from the collection bag 1 through conduit 25 into the plasma satellite bag 4, and the flow is stopped before buffy coat passes into the conduit 25. The machine then operates to express the red cells from the collection bag 1 into the transfer bag 3. The buffy coat remains in the collection bag 1. The line 23 between the filter device 10 and the transfer bag 3 is clamped, and the machine operates until the cycle is completed. The SAGM bag 2 and the collection bag 1 are then removed from the expressor pins and placed on the counter top. The transfer bag 3, that now contains the red cells and SAGM additive, as well as the air that is displaced from the bags and tubing, is hung above the filter device 10 to provide a sufficient gravity head for filtration. The clamp is opened, and the fluid containing red cells and SAGM is passed through the leukocyte depletion filter 10, entering via the inlet, and exiting via the outlet. The leukocyte depleted fluid passes from the outlet into the SAGM bag 2 , and the fluid is stored in the bag until needed.

While the invention has been described in some detail by way of illustration and example, it should be understood that the invention is susceptible to various modifications and alternative forms, and is not restricted to the specific embodiments set forth. It should be understood that these specific embodiments are not intended to limit the invention but, on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the claims .

Claims

1. A method for processing a biological fluid comprising simultaneously compressing a first container (1) and a second container (2) with a single pressure differential, the first container (1) including a biological fluid, and the second container (2) including a non-biological fluid, wherein the non-biological fluid is compatible with the biological fluid.

2. A method according to claim 1, and further comprising simultaneously passing at least a portion of biological fluid from the first container (1) , and at least a portion of a non-biological fluid from the second container (2) , wherein the pressure from said simultaneous compression provides for the simultaneous passage of the portions of the fluid.

3. A method according to claim 1 or claim 2 wherein the single pressure differential is provided by a single plate or by a chamber containing the first container (1) and the second container (2) .

4. A method according to any one of claims 1 to 3 wherein a biological fluid filter device (10) is interposed between the first container (1) and the second container (2) , the method comprising passing simultaneously at least a portion of the biological fluid from the first container (1) , and at least a portion of the non- biological fluid from the second container (2) and through the biological fluid filter device (10) .

5. A method according to any one of claims 1 to 4 and comprising passing at least a first portion of biological fluid from the first container (1) , and passing a second portion of the biological fluid from the first container (1) , said second portion comprising red blood cells.

6. The method of claim 5, wherein the first container (1) includes at least first and second ports, the method including passing the first portion of biological fluid through the first port, and passing the second portion of biological fluid through the second port .

7. The method of any one of claims 1 to 6, including passing at least a portion of the biological fluid and at least a portion of the non-biological fluid into a third container (3) .

8. The method of claim 5 or 6, including passing the second portion of the biological fluid and the non-biological fluid into a third container (3) .

9. The method of any one of claims 1 to 8 , wherein creating a pressure differential includes activating an expressor having a single movable plate.

10. The method of any one of claims 1 to 8 wherein creating a pressure differential comprises placing the first container (1) and the second container (2) in a chamber (305) , and then introducing a fluid into the chamber (305) exterior to the containers (1,2) to vary the volume of the containers (1,2) .

11. The method of claim 1, including passing at least a portion of biological fluid from the first container (1) , and then passing at least a portion of non-biological fluid from the second container (2) .

12. The method of any one of claims 1 to 10, wherein the non- biological fluid and a portion of the biological fluid contact each other and form a fluid mixture, and the method further comprising depleting leukocytes from the mixture .

13. The method of claim 12, wherein depleting leukocytes from the mixture includes passing the mixture through a biological fluid filter device (10) comprising a leukocyte depletion filter.